1. Field of the Invention
The present invention relates to a number of innovative electrophilic substitution reactions involving 2,5-dithienylpyrrole (2,5-DTP). More specifically, these reaction are used in the synthesis of monomers which in turn can be used to synthesize functionalized conducting organic polymers.
2. Discussion of the Prior Art
I. Organic Conducting Polymers
The present case relates to and is an improvement of U.S. Ser. No. 114,011, now U.S. Pat. No. 4,886,623, "Functionaized Conducting Polymers and Their Use in Diagnostic Devices" by Albarella, et al. The Albarella patent application is hereby incorporated by reference.
Organic conducting polymers are synthesized from specialized monomers which are polymerized chemically, such as in the synthesis of polyacetylene, or electrochemically, such as in the synthesis of polypyrrole and polythiophene. Once polymerized, conducting polymers can be covalently functionalized with an enzyme, antigen or an ion specific binding site. The resulting functionalized conducting organic polymer can be used in diagnostic assays to selectively determine the presence and concentration of a specific analyte.
Functionalized conducting polymers can determine an analyte by measuring the change in conductivity of the polymer. The change in conductivity can arise either from the transduction of vibrational excitation (which is induced in the covalently-bound functionality by the reaction of the functionality with the analyte) or alternatively from secondary reaction effects between the covalently bound functionality and the analyte, such as in the generation of hydrogen peroxide.
Conducting polymers can also be useful in technical fields relating to batteries, display devices, corrosion prevention in metals and semiconductors and in microelectronic devices such as diodes, transistors, sensors, light emitting devices and energy conversion and storage elements. However, present day organic conducting polymers possess several limitations that have hindered the expansion of these substances into these and other potential applications.
II. Design Considerations In Synthesizing Conducting Polymers
Conducting organic polymers are generally amorphous, disordered materials. Therefore if bulk conductivity is to be sustained, charge transport must occur between the polymer strands as well as along single polymer strands. The probability of interchain charge transport is directly related to the distance between the chains, and the distance between polymer chains is acutely sensitive to and dependent upon the nature and size of the dopant counterion and the character and steric requirements of the substituents.
The electronic and steric effects introduced by a conducting polymer's substituents can substantially change the polymer's conductivity. For example, in conducting polymers having heteroaromatic ring monomer units, the substituted five or six member heteroaromatic ring can be more conducting or less conducting than the unsubstituted parent heteroaromatic compound, depending upon electronic and steric effects.
III. Polyacetylene: Among The First Organic Conducting Polymers To Be Synthesized And Studied
Polyacetylene is prepared chemically from acetylene by using an appropriate catalyst. As prepared chemically, polyacetylene is an insulator, exhibiting conductivities in the range of 10.sup.-10 to 10.sup.-13 S/cm (Siemens per centimeter) that correspond to the conductivity of known insulators, such as glass and DNA.
However, polyacetylene can be "doped" using a variety of oxidizing or reducing agents, such as antimony pentafluoride, the halogens, or aluminum chloride. By doping, polyacetylene is converted into a highly conducting polymer, exhibiting a conductivity of approximately 10.sup.3 S/cm, similar to the conductivity of metals such as bismuth. However, polyacetylene suffers from the drawbacks of extreme instability in air and a precipitous drop in conductivity whenever an acetylenic hydrogen is replaced by an alkyl or similar-type substituent group.
IV. Polypyrrole: Relatively Stable But A Precise Physical Structure Is Necessary To Provide Useful Conductivity
Polypyrrole, a conducting polymer similar to polyacetylene, can be synthesized chemically or electrochemically and is more stable than polyacetylene. However, polypyrrole exhibits conductivity ranging from about 1 S/cm to about 100 S/cm and the conductivity can change dramatically, depending upon the precise composition and physical structure of the polypyrrole.
Alkyl groups on either the nitrogen or the carbons of the heteroaromatic pyrrole ring decreases the conductivity of polypyrrole. For example, an unsubstituted polypyrrole, incorporating the teterafluoroborate anion as the compensating counterion, exhibits a conductivity of 40 S/cm, whereas the N-methyl derivative, incorporating the same dopant, exhibits a conductivity of 10.sup.-3 S/cm; the 3-methyl derivative of pyrrole exhibits a conductivity of 4 S/cm; 3,4-dimethyl derivative has a conductivity of 10 S/cm; and the 3,4-diphenyl derivative exhibits a conductivity of 10.sup.-3 S/cm.
The conductivity decrease in substituted polypyrroles is attributed to several factors. First, the substituent introduced onto the heteroaromatic pyrrole ring cannot alter the oxidation potential of the parent heteroaromatic to the extent that electropolymerization at the anode is precluded. Secondly, the aromatic pi-electron system of the parent heterocycle must be maintained. Disruption of the pi-electron system of the heteroaromatic ring will adversely affect the relative stability of the aromatic and quinoid-like forms and therefore seriously reduce conductivity. A third critical consideration is that the functionality introduced onto the parent heterocycle must not create steric demands that preclude the adoption of a planar configuration by the conducting polymer.
This planar configuration requirement is significant. Numerous N-alkyl and N-aryl derivatives of polypyrrole have been prepared and discussed in the literature. However, even the simplest of these N-substituted polypyrroles, poly-N-methylpyrrole, exhibits conductivities that are three orders of magnitude lower than unsubstituted polypyrrole files doped with the same counterion. It is also possible to produce thin films of poly-N-aryl pyrroles, wherein the phenyl group is further substituted in the para position. However, polymers produced from these N-aryl pyrroles invariably exhibit conductivities three or more orders of magnitude less than the parent unsubstituted pyrrole. Such low conductivities preclude the use of these substituted polypyrroles in the development of analyte sensors.
The steric interaction introduced by the pyrrole ring substituents is important because of the mechanism of charge transport through the conducting polymer system. In one charge transport mechanism, electric charge is conducted through the polymer chain itself because of bipolaron structures that exist along the polymer chain. The bipolaron structures are defects occurring in the polymer lattice wherein two dopant counterions from the supporting electrolyte balance two positive centers found in the polymer.
Generally, the two positive centers are spaced, and confined, by approximately four monomer units and these defects serve to transport charge along the polymer chain. However, in order to transport charge along the chain, the compositions must be planar, such that the charge can be transported along the planar pi-electron system of the chain. If a substituent is sufficiently large, the steric interaction between constituents can distort the pyrrole monomer units out of planarity, thereby destroying the planarity of the pi-electron system, and destroying or seriously reducing the conductivity of the polymer.
Polymer substituents should not be strongly electron withdrawing or strongly electron-donating, as strong electronic effects can serve to destroy conductivity. However, especially for N-substituted pyrroles, the steric interactions, not electronic effects, are the main factor in determining polymerability, polymer conductivity and cyclic stability of the polymer between the doped and undoped state. Steric interactions in polypyrrole derivatives are more dominant because the predominant destabilizing interactions in pyrrole derivatives involve the hydrogen atom of the pyrrole nitrogen.
The synthesis and conductivities of polypyrrole and substituted polypyrroles have been extensively investigated as seen in the general references cited below. These references include the information discussed above and general information concerning the polypyrroles such as that the specific dopant can seriously affect the conductivity of the polymer; that conductivity is observed only for alpha-alpha coupling of monomers and not for alpha-beta coupling of monomers; and that polypyrrole films are stable, insoluble, and inert to most reagents, except possibly treatment by alkalis. The conductivity and stability of polypyrrole makes polypyrrole a good candidate for use in analyte sensors, if the polypyrrole conductivity can be maintained when functional groups are introduced onto the heteroaromatic ring.
The representative references discussing the polypyrroles include
G. Bidan, Tet. Lett., 26(6):735-6 (1985).
P. Audebert, et al, J. C. S. Chem. Comm., 887 (1986);
M. Wrighton, Science, 231:32 (1986);
R. Simon, et al., J. Am. Chem. Soc., 104:2034 (1982);
Diaz, et al., J. Electroanal. Chem., 133:233 (1982);
Saloma et al., J. Electrochem. Soc., 132:2379 (1985);
Rosenthal, et al., J. Electroanal. Chem. and Interfac. Chem., 1:297 (1985);
Bidan, et al., Synth. Met., 15:51 (1986);
Salmon, et al., J. Electrochem. Soc., 1897 (1985);
Genies et al., Synth. Met., 10:27 (1984/85).
Bidan, et al., Nouveau Jour. De Chimie, 8:501 (1984);
Travers, et al., Mol. Cryst. Liq. Cryst., 8:149 (1985).
V. Polythiophene: Relatively Stable But Also Requires Precise Physical Structure For Useful Conductivity
Another well studied conducting polymer is polythiophene, wherein thiophene is electrochemically polymerized to yield a stable conducting polymer. Polythiophene resembles polypyrrole in that polythiophene can be cyclized between its conducting (oxidized) state and its nonconducting (neutral) state without significant chemical decomposition of the polymer and without appreciable degradation of the physical properties of the polymer. Polythiophene, like polypyrrole exhibits conductivity changes in response both to the amount of dopant and to the specific dopant, such as perchlorate, tetrafluoroborate, hexafluorophosphate, hydrogen sulfate, hexafluoroarsenate and trifluoromethylsulfonate.
Substituents placed on the heteroaromatic thiophene ring can affect the resulting conducting polymer. For example, thiophene polymerization can be affected by large substituents at the 3 and 4 positions, as seen in the inability of 3,4-dibromothiophene to polymerize. The electronic and steric effects introduced by the 3,4-dibromo substituents may prevent chain propagation. However, in contrast to pyrrole, ring substituents on thiophene do not seriously reduce the conductivity of the resulting heteroaromatic polymer.
The following are representative references concerning the synthesis and conductivity of polythiophene and substituted polythiophenes:
Tourillon, "Handbook of Conducting Polymers," Skotheim, ed., Marcel Dekker, Inc., New York, 1986, 293;
Waltham et al., J. Phys. Chem., 87:1459 (1983);
Tourillon et al., J. Polym. Sci. Polym. Phys. Ed., 22:33 (1984);
Tourillon et al., J. Electroanal. Chem., 161:51 (1984);
Diaz et al., "Handbook of Conducting Polymers," Skotheim, ed., Marcel Dekker, Inc., New York 1986, p. 81.
Bargon, et al., J. Res. Dev., 27:330 (1983);
Tourillon et al., J. Phys. Chem., 87:2289 (1983); and
Czerwinski, et al., J. Electrochem. Soc., 2:2669 (1985).
Bryce, Chissil, Kathirgamanathan, Parker, and Smith, J. C. S. Chem. Soc., 466 (1987).
The following references disclose the preparation and utility of internally doped (self-doped) conducting polymer films. These polymers may allow for highly ordered and therefore conductive films, as the potential counterions are covalently bound to the polymer backbone, instead of randomly diffused between polymer chains.
Patil, Ikenoue, Wudl, and Heeger, J. Amer. Chem. Soc., 109:1858 (1987) discloses the preparation of sodium poly(3-thiophene-beta-ethanesulfonate) and sodium poly(3-thiophene-delta-butanesulfonate) internally doped films from their respective thiophene monomers.
Mager, Wudl, Patil, Ikenoue and Colaneri, 193, ACS National Meeting, April 5-10, 1987, Denver, Colo., Anal. Chem. Abstract #102 and Patil, et al., Synthetic Metals, 20:151 (1987) discloses self-doped conducting polymers.
VI. Poly[2,5-di(2-thienyl)-pyrrole]
McLeod, et al., Polymer, 27(3):455-8 (1986), discloses the synthesis and polymerization of functionalized 2,5-dithienylpyrrole (2,5-DTP) derivatives, including the electrochemical polymerization and the properties of the parent molecule, poly[2,5-di(2-thienyl)-pyrrole]. The primary objective of the McLeod article however was to determine the solubility of the polymer resulting from 2,5-DTP.
a. 2,5-DTP
The most common method of synthesizing 2,5-DTP is described in Wynberg and Metselaar, Syn. Comm., 14:1 (1984). This method is illustrated below in TABLE 1.
TABLE 1 __________________________________________________________________________ ##STR1## ##STR2## ##STR3## __________________________________________________________________________
A modified version of this "Wynberg" method disclosing a method of preparing asymmetrical 2,5-dithienylpyrroles is shown in Phillips, Hebert, and Robichaud, Syn. Comm., 16:411 (1986). However, the Phillips method, as well as the other methods identified below, are also rather complex, particularly in terms of large scale manufacturing.
Kooreman and Wynberg, Recueil 86:37 (1967) describes the synthesis of a terthienyl oligomer prepared using a Stevens rearrangement of N,N-di(thenoylmethyl)-N,N-dimethylammonium salt as a key step in the synthesis.
b. Electrophilic Substitution Reactions of Pyrroles and Thiophenes
Xu, Anderson, Gogan, Loader, and McDonald, Tet. Lett., 22:4899 [1981) and Rokach, Hamel, Kakushima, and Smith, Tet. Lett., 22:4901 (1981) disclose the use of N-benzenesulfonyl blocking groups to direct electrophilic substitution reactions of pyrrole to the 3-position.
Muchowski and Salas, Tet. Lett., 24:3455 (1983), discloses the directing effect of the N-triisopropyl blocking group in the preparation of 3-substituted pyrrole derivatives.
Anderson and Loader, Synthesis, 353 (1985) summarizes conventional methodologies for the preparation of 3-substituted pyrroles from pyrrole.
The above identified references exemplify that the present state of the art is directed to electrophilic substituion reactions using N-1 pyrrole blocking groups to direct the reaction to the pyrrole C-3 position. Such a reaction scheme, however, requires additional manipulations and can be unduly complex and burdensome to manufacture on a large scale. Furthermore, such a reaction scheme often does not achieve optimal regioselectivity towards functionalization at the pyrrole 3-position.
c. 2,5-DTP Reactions
The 2,5-DTP monomer is a pyrrole having a thiophene group in the 2 and the 5 position, and therefore electrophilic substitution can occur at a number of positions along the thiophene groups or at the 1, 3, or 4 position of the pyrrole group.
The substitutent groups, pyrrole and thiophene, are heterocyclic compounds. Except for a general tendency to undergo addition reactions, these heterocycles do not have the properties expected of a conjugated diene or an amine or thioether. Thiophene does not undergo the oxidation typical of a sulfide, and pyrrole does not possess the basic properties typical of amines.
Instead, these heterocycles and their derivatives most commonly undergo electrophilic substitution: nitration, sulfonation, halogenation, Friedel-Crafts acylation, even the Reimer-Tiemann reaction and coupling with diazonium salts. For pyrrole, the nitrogen's extra pair of electrons (which is responsible for the usual basicity of nitrogen compounds) is involved in the pi electron cloud and is not available for sharing with acids. In contrast to most amines therefore pyrrole is an extremely weak base. By the same token, however, there is high electron density in the ring which causes pyrrole to be extremely reactive toward electrophilic substitution.
For thiophene, sulfur carries an unshared pair of electrons in a sp.sup.2 orbital. The sulfur atom provides two electrons for the pi cloud and as a result is also extremely reactive toward electrophilic substitution.